Our major goal is to determine the physiological role and the mechanism of cell cycle dependent expression of receptors for melanotropin in normal melanocytes and melanoma cells. We have shown previously that MSH receptors are expressed in the G2 phase of the cell cycle and that treatment with neuraminidase "unmasks" latent receptors in G1 and S. Next, we want to determine whether the enzyme acts directly on the receptors or, alternatively, whether the effect is an indirect one. At 37~C, the hormone-receptor complex is quickly internalized, and the labeled hormone appears in the premelanosomes and the nucleus within hours. Since MSH-induced elevation of intracellular tyrosinase levels is caused by a de novo synthesis of the enzyme, the hormone appears to have an effect on the expression of genes coding for the enzyme. We will investigate the nuclear target of MSH action in melanoma cells. The effect of growth controls on the expression of MSH receptors and on hormone-induced melanization will be studied. The information obtained from these studies will be used for developing a site-directed (MSH receptor-mediated) chemotherapy of melanomas. Inhibitors of the cell cycle will be used to prevent cell-cycle related evasion of melanoma cells from site-directed chemotherapy.